lacosamide and stiripentol

There is a need for newer anti-epileptic drugs (AEDs) with improved efficacy and tolerability. This article reviews AEDs introduced since 2007 and investigational compounds in clinical development.. Two recently introduced AEDs, stiripentol and rufinamide, have been licensed exclusively for orphan indications, that is severe myoclonic epilepsy of infancy (stiripentol, Europe) and Lennox-Gastaut syndrome (rufinamide, Europe and the USA). This signals a welcome new trend to explore novel treatments in specific pediatric syndromes for which there are high therapeutic needs. Two additional AEDs, lacosamide and eslicarbazepine acetate, have been licensed recently for a more traditional indication, refractory partial-onset seizures. Although newly introduced agents given as adjunctive therapy have been found to be superior to placebo in reducing seizure frequency, the ultimate goal of sustained seizure freedom is rarely achieved. Therefore, the search for better agents should continue. Several investigational compounds are currently in various stages of clinical development.. The recent introduction of newer AEDs has enlarged the armamentarium against epilepsy. However, newer agents had only a modest impact on the probability of achieving long-term remission. Novel strategies for the discovery and development of truly innovative AEDs are sorely needed.

Topics: Acetamides; Anticonvulsants; Clinical Trials as Topic; Dioxolanes; Drug Approval; Drug Discovery; Epilepsy; Humans; Lacosamide; Remission Induction; Triazoles

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1β2γ2 GABA

Topics: Allosteric Regulation; Animals; Anisoles; Anticonvulsants; Carbamazepine; Cinnamates; Dioxolanes; Drug Design; Drugs, Chinese Herbal; Esters; Humans; L-Lactate Dehydrogenase; Medicine, Chinese Traditional; Mice; Molecular Structure; Neuralgia; Polygala; Receptors, GABA-A; Structure-Activity Relationship; Valproic Acid